Dr. Shetty's current research primarily comprises three themes: (1) Mechanisms by which neural stem/progenitor cell (NSC) grafts ease seizures and memory and mood dysfunction in prototypes of chronic temporal lobe epilepsy (TLE): Previous work from Dr. Shetty's lab has shown that grafting of NSCs into the hippocampus of animals displaying spontaneous recurrent seizures (SRS) for an extended period of time (a model of drug-resistant epilepsy) has promise for reducing the frequency and intensity of SRS. Additional studies have shown that early intervention with grafting of GABA-ergic cells or NSCs restrains epileptogenic changes and the development of chronic epilepsy after status epilepticus. His current research is focused on further refining the neural cell grafting therapy for TLE. A project funded by the VA (Combined NSC Grafting and Neurogenic Drug Therapy for Temporal Lobe Epilepsy) investigates the long-term survival and functional effects of NSC grafts (derived from the embryonic rat medial ganglionic eminence) in a rat model of TLE, when grafted into the hippocampus along with two weeks peripheral administration of therapeutic compounds such as fibroblast growth factor-2 or neurosteroid ganaxolone. Another project funded by the DOD (Human iPSC-derived GABA-ergic Precursor Cell Therapy for Chronic Epilepsy) examines the efficacy of human GABA-ergic progenitors (derived from human induced pluripotent stem cells) for easing seizures and improving cognitive and mood function in a rat model of chronic TLE. (2) Elucidating pathophysiological changes and examining the efficacy of promising compounds/drugs for easing cognitive and mood dysfunction in Gulf War Illness (GWI): A project funded by the VA (Memory and Mood Enhancing Strategies for GWI) examines mechanisms of brain dysfunction in a rat model of GWI. The results have shown that combined exposures to moderate doses of the anti nerve gas drug pyridostigmine bromide and pesticides (DEET and permethrin) with or without mild stress cause memory and mood dysfunction. Importantly, these changes are linked with declined neurogenesis (a substrate for maintaining normal memory and mood function), NSC dysfunction, chronic low-grade inflammation, increased oxidative stress and loss of GABA-ergic interneurons in the hippocampus. Recent studies have evaluated the efficacy of natural anti- inflammatory compounds (Resveratrol and Curcumin) and antidepressant therapy (voluntary physical exercise) for reversing memory and mood impairments through enhancement of neurogenesis and suppression of inflammation and oxidative stress. These studies have provided interesting positive results, which are currently in preparation for publications. Another recent project funded by the DOD (Monosodium Luminol for Improving Brain function in GWI) examines the efficacy of monosodium luminol (a drug that maintains redox homeostasis) in an animal model of GWI. (3) Examining novel neuroprotective approaches that prevent the evolution of an initial injury into cognitive and mood dysfunction, using models of traumatic brain injury (TBI): The current studies (supported by Emerging Technology Funds from the State of Texas) are focused on two mouse models of TBI, which include a moderate TBI induced by controlled cortical Impact injury, and a mild TBI induced by exposure to blast shock waves (BSWs). Recent studies have suggested that single exposure to BSWs causes long-term cognitive and mood dysfunction associated with decreased neurogenesis in the hippocampus. Additional studies examine the efficacy of several approaches for preventing functional deficits in TBI prototypes. These include administration of anti-inflammatory compounds and exosomes derived from human mesenchymal stem cells.
The PI's research projects have high relevance for Veterans' health. Neural stem cell grafting studies for temporal lobe epilepsy (TLE) have significance, as there is a growing concern that head injuries among soldiers returning from Iraq and Afghanistan could result in epilepsy in the coming years. Cell grafting studies in PI's lab have the promise to serve as a useful therapy for intractable epilepsy but needs careful appraisal of lasting efficacy in animal prototypes before a possible clinical application. Studies in animal models of Gulf war illness (GWI) have relevance for developing a therapy for memory and mood dysfunction in GWI, which afflicts ~30% of 700,000 veterans who served in the Persian Gulf war-1. Traumatic brain injury (TBI) studies in blast injury models have importance towards developing treatment modalities for people afflicted with mild TBI, which is a signature brain injury for veterans served in Iraq and Afghanistan wars.
